Immunology Flashcards
What are the differences between the innate and adaptive immune systems?
Innate is quick to respond Adaptive is more specific Innate is present at birth Adaptive has good memory Innate detects alterations in haemostasis Adaptive is humoral and cell mediated
What innate immunological cells are there?
Blood -monocyte -basophil -eosinophil -neutrophil -natural killer cell Tissue -dendritic cells -macrophages -mast cell
How do macrophages, dendritic and mast cells affect invading cells?
They release cytokines to attract other cells and dilates the arteries to get more blood flow, and get adhesions to stick things
Can phagocytose cells
What are the functions of the innate system?
Phagocytosis
Antigen presentation to communicate between the adaptive system
Natural killer cell releases perforin and granzyme
Inflammation
Opsonisation
What is MHC1 and 2?
MHC1- all nucleated cells have it (and platelets which don’t have nucleus), recognised by CD8
MHC2- antigen presenting cells have it, recognised by CD4
Major Histocompatibility Complex
What are the cells of the adaptive immune system?
T cells (helper, regulatory and cytotoxic) B cells (can differentiate into plasma cells)
What are cytokines and what do they do?
Large and heterogeneous soluble proteins
Communication system – act locally or at a distance
Regulate and co-ordinate the cells of innate and adaptive immunity ie regulate immune responses
Produced during normal haematopoiesis
Produced in response to microbes, tissue damage or other antigens
Produced by many cell types – esp macrophages and T helper cells
How do CD8 cells kill other cells?
The cytokines produced by the CTL do not cause killing of the cell directly, they will e.g. induce the actions of phagocytic clearance.
CD8 cells kill via perforin and granzyme or FasL pathway
How do Natural killer cells kill other cells?
If MHC presentation is normal then NK cells will leave alone, but if too low (cancer) or not wrong then NK will induce apoptosis
Same killing mechanism as CD8
When in life does each antibody start being produced?
IgM produced as fetus, IgG not til birth, IgA not until 1-2 months after birth
Breast milk contains IgA
What is the activity of the complement immune system>
Chemotaxis of phagocytes to sites of inflammation
Opsonisation
Lysis of micro-organisms
Maintain solubility of Ag / Ab complexes
What lineage is the natural killer cell from?
Lymphoid (but involved in innate immune system)
What is involved in the process of negative and positive selection in T lymphocytes?
Positive selection involves selecting T lymphocytes with T cell receptors capable of interacting appropriately with host MHC molecules. If the double positive thymocytes are able to interact with the MHC, they survive. If they are unable to interact with the MHC, they are destroyed by apoptosis. Negative selection involves identifying thymocytes that interact too strongly with self antigens within the thymus. Thymocytes that react too strongly, are destroyed by apoptosis
How are T regulatory cells formed and what do they do?
During selection of T cells in the thymus, some T cells that recognise self-antigens are not deleted and differentiate into regulatory T cells that are specific for that antigen. They are responsible for suppressing the activation, proliferation and cytokine production of CD4 and CD8. They control the response to self-antigens, and in this way monitor the process of self-tolerance. They secrete IL-10 and Transforming growth factor-beta (TGF-b), which are anti-inflammatory and help to suppress the immune response.
What cells produce antibodies?
Plasma cells
Which antibody is a pentomer?
IgM
What are the functions of antibodies?
They can bind to antigens directly to form immune complexes, which can be cleared through filtration of the blood in organs like the liver and spleen.
Antibodies also act as opsonins for phagocytosis. Antibodies are capable of activating the complement cascade via the Classical pathway.
Antibodies can bind to target cells and initiate a non-phagocytic cell-mediated destruction of these cells. This is called Antibody-dependent cellular cytotoxicity (ADCC)
What antibody provides a primary and secondary response with the secondary response being larger?
IgG
What is the immunological memory?
After the primary infection by a pathogen, a small pool of long-lived memory B and T cells specific to the pathogen’s antigen remain quiescent within the body. Memory cells can lie dormant for many years but are poised to respond rapidly if reinfection occurs.
Name two pattern recognition receptors
Toll-like receptors (TLRs)
C-type lectin receptors (CLRs)
What cells can phagocytose other cells?
Macrophage Dendritic cell Monocyte Mast cell Neutrophil
What are three pathways that can activate the complement cascade?
Classical pathway (antibodies and antigens)
Lectin pathway
Alternative pathway
What pathogen does each immune cell target?
Neutrophils – bacterial & fungal infection
Monocytes – fungal infection
Eosinophils – parasitic infections
T lymphocytes – fungal & viral infection, PJP
B lymphocytes – bacterial infection
What is G-CSF used for?
G-CSF is used to reduce neutropenia
What drugs should be used to treat a neutropenic sepsis?
Broad spectrum I.V. antibiotics
- Tazocin and Gentamicin
If a gram positive organism is identified add vancomycin or teicoplanin
If no response at 72 hours add I.V. antifungal treatment e.g. Caspofungin
What are the two types of immunodeficiency?
Primary, or congenital, immunodeficiencies
Secondary, or acquired, immunodeficiencies
What are patients more susceptible to if they are immunodeficient?
The major consequence of immunodeficiency is increased susceptibility to infection.
Patients with immunodeficiencies are also susceptible to certain types of cancer.
Certain immunodeficiencies are associated with an increased incidence of autoimmunity
What immune defect is present if there is repeated infection with an encapsulated bacteria?
defective antibody production.
What immune defect is present if there is repeated respiratory infection by pneumococcus orHaemophilusspp?
Antibody deficiency (IgG and IgA
What immune defect is present if there is repeated infection with staphylococci, gram-negative bacteria, and fungi?
Reduced number or function of phagocytes
What immune defect is present if there is repeated infection with Neisseria meningitidis?
Complement defect
What immune defect predisposes to infection with intracellular organisms such as protozoa, viruses, and intracellular bacteria, including mycobacteria?
Defects in T cells or macrophages
What is a polymorphism?
Polymorphism involves one of two or more variants of a particular DNA sequence. The most common type of polymorphism involves variation at a single base pair.
Not called a mutation if happens in over 1% of the population
What is SCID?
Many mutations result in severe combined immunodeficiency (SCID), a group of disorders that affect both T and B cells.
Infants with SCID die in the first few months of life unless treatment is given.
Some are autosomally inherited and there may be a history of consanguinity.
Other types are X-linked and there may be a history of early deaths in maternal uncles.
Stem cell transplant can cure SCID but it has to be done quickly.
What immune defect is present in DiGeorge syndrome?
22q11 deletion
Loss of T cells and reduced serum Ig
What is CVID?
Common variable immunodeficiency (CVID) is a common polygenic disorders that affects antibody production.
Patients have low levels of total IgG. Levels of IgA and IgM and numbers of B and T cells are variable.
CVID causes recurrent respiratory tract infections.
Infections that involve the gut, skin, and nervous system also occur.
Autoimmunity is common in CVID.
Autosomal-recessive inheritance.
What is a hypersensitivity reaction?
Excessive immune responses that cause damage
What is a Type 1 hypersensitivity reaction?
Mediated through the degranulation of mast cells and eosinophils.
The effects are felt within minutes of exposure.
Immediate hypersensitivity, allergy
What are the causes of a type one hypersensitivity reaction?
Filaggrin is expressed by keratinocytes and involved in maintaining epithelial barriers and moisturizing surfaces and controlling pH.
Polymorphisms in the gene encoding is established as a cause of allergy and implicated in 50% of severe eczema.
Exposure to environmental factors adds the risk of developing allergies.
Timing is important.
How does a skin prick test work?
To provide a control, a histamine solution is applied at position 1, and saline is applied at position 2. These are pricked through the dermis, and 10 minutes later the histamine has given a positive reaction; this would not have happened had the patient recently taken an antihistamine. The saline has given no reaction, which confirms the patient’s skin does not simply react to trauma.
What is a type 2 hypersensitivity reaction?
Antibody mediated hypersensitivity
IgG or IgM reacting with antigen present on the surface of cells.
The bound Ig interacts with complement or with Fc receptor on macrophages.
Opsonisation of target cells
Immune mediated haemolysis.
Takes several hours.
Autoimmune haemolytic anaemia could be induced by infections or drugs
Part of a systematic autoimmune disease (SLE)
Autoantibodies produces by malignant B cells
Grave Disease
Myasthenia Gravis
Goodpasture syndrome
Pernicious anaemia
What is a type three hypersensitivity reaction?
Immune complex disease, if not cleared by the complement system then get reaction
IgG is also responsible for type III hypersensitivity.
Immune complexes of antigen and antibody form and cause damage at the site of production or circulate and cause damage elsewhere.
Takes time to form
Glomerulonephritis
SLE
What is a type four hypersensitivity reaction?
The slowest form of hypersensitivity is that mediated by T cells. This can take 2 to 3 days to develop Delayed hypersensitivity Rheumatoid arthritis Multiple Sclerosis
What is immunological tolerance?
Immunologic tolerance: unresponsiveness to an antigen that is induced by previous exposure to that antigen.
The same antigen may induce an immune response or tolerance, depending on the conditions of exposure and the presence or absence of other stimuli.
Antigens that induce tolerance are called tolerogens, or tolerogenic antigens
What is autoimmunity?
Adaptive immune responses to self antigens
Tolerance to self antigens, also called self-tolerance, is a fundamental property of the normal immune system, and failure of self-tolerance results in immune reactions against self (autologous) antigens.
Such reactions are called autoimmunity, and the diseases they cause are called autoimmune diseases.
Autoimmune disease occurs when autoreactive T cells or autoantibodies cause tissue damage through hypersensitivity reaction types II, III and IV
What are two types of immunological tolerance?
Central tolerance- The thymus plays an important role in eliminating T cells with high affinity to self-antigens
Bone marrow is important in B cell tolerance
Peripheral tolerance- Mature lymphocytes that recognize self antigens in peripheral tissues become incapable of activation or die by apoptosis
What are autoantibodies?
Antibodies directed at normal cellular components, referred to asautoantigens
What is molecular mimicry?
Structural similarity between self-proteins and microbial antigens may trigger an autoimmune response.
What are the two ways to manage an autoimmune disease?
Suppression of the damaging immune response
Replacement of the function of the damaged organ
What types of transplant are there?
Autologous transplantrefers to tissue returning to the same individual after a period outside the body, usually in a frozen state. (safest)
Syngeneic transplantrefers to transplant between identical twins; there is usually no problem with graft rejection. Also called isograft.
Allogeneic transplanttakes place between genetically nonidentical members of the same species; there is always a risk of rejection.
Cadaveric transplantationuses organs from a dead donor.
Xenogeneic transplanttakes place between different species and carries the highest risk of rejection.
What is rejection in transplants?
Rejectionrefers to damage done by the immune system to a transplanted organ.
What are the criteria for getting a solid organ transplant?
There must be good evidence that the damage is irreversible
That alternative treatments are not applicable.
The disease must not recur.
Mortality risk on and off transplant list
No infection
Psychological health
How is the chance of rejection in a solid organ transplant reduced?
The donor and recipient must be ABO compatible.
The recipient must not have anti-donor human leukocyte antigen (HLA) antibodies.
The donor should be selected with as close as possible HLA match to the recipient.
The patient must take immunosuppressive treatment.
Negative serum cross match with donor’s T cells
What is a hyperacute reaction in a solid organ transplant?
Within hours of transplantation
Preformed antibodies binding to either ABO blood group or HLA class I antigens on the graft.
Antibody binding triggers a type II hypersensitivity reaction, and the graft is destroyed by vascular thrombosis.
Hyperacute rejection can be prevented through careful ABO and HLA cross-matching and is now rare.
What is an acute reaction to a solid organ transplant?
Type IV (cell-mediated) delayed hypersensitivity reaction
Takes place within days or weeks of transplantation.
Donor dendritic cells stimulate an allogeneic response in a local lymph node and T cells proliferate and migrate into the donor kidney.
HLA incompatibility is the main cause. Minimising any HLA mismatch of the donor and recipient can reduce acute rejection.
Shortage of donor kidneys leads to using a partially mismatched kidney.
The survival of the kidney is related to the degree of mismatching, especially at the HLA-DR loci
Could be antibody mediated rejection.
What is a chronic reaction to a solid organ transplant?
Chronic rejection takes place months or years after transplant.
An element of allogeneic reaction is often mediated by T cells, which can result in repeated acute rejection.
Chronic rejection may be caused by recurrence of pre-existing autoimmune disease.
What investigation is done to check if the organ is being rejected?
Try as much as possible to do a biopsy but this cant always happen
What is the immunopathological mechanism for rejection of a graft?
Afferent phase: donor MHC molecules on ‘passenger leukocytes’ (dendritic cells) within the graft are recognised by the recipient’s CD4+ T cells (allorecognition).
Effector phase: CD4+ T cells recruit effector cells responsible for the tissue damage of rejection; macrophages, CD8+ T cells, NK cells and B lymphocytes.
Not all parts of the graft need to be attacked for rejection to occur.
What is autologous stem cell transplant?
Marrow is removed, frozen, and reinfused after potent chemotherapy has been given.
Autologous transplants carry minimal immunologic risk.
When are allegenic stem cell transplants carried out?
Much riskier than autologous
Hematologic malignancy
Cases when myeloid cell production is reduced or notably abnormal, such as in aplastic anemia
Primary immunodeficiencies such as severe combined immunodeficiency (SCID)
What are the three sources of stem cells?
Bone marrow
Peripheral blood
Umbilical cord blood
What is conditioning in a stem cell transplant?
High dose chemotherapy
High dose radiotherapy
Destroy the recipient’s stem cells and allows the engraftment of donor cells
What immunosuppressive drugs can be used in transplantation?
Corticosteroids affect antigen presenting cells and T cells
Cyclosporine and tacrolimus affect proteins in T cell cascade
Monoclonal antibodies and Rapamycin affect IL-2
Azathioprine stops DNA synthesis
What is Ig used to treat?
Plasma-derived IgG is a key biologic for replacement therapy in primary and secondary immunodeficiency disorders
Also used for some autoimmune disorders
Polyclonal IgG preparation usually given intravenously (IVIg) but can also be applied subcutaneously (SCIg)
What are the two types of immunotherapy?
Direct therapy-Antibodies or antibody related fragments that detect an antigen on the tumour cell and destroy the target either by recruiting immune cells or by delivering a toxin or radioisotope to it. Target is the tumour
Indirect therapy- The immune system is activated rendering it able to seek and destroy tumour cells Target is the immune system
Name some direct immunotherapies
Monoclonal antibodies
Chimeric antigen receptors
(CARs)
Bi-specific antibodies
Name some indirect immunotherapies
Tumour vaccines Dendritic cell vaccines Adoptive cell transfer Cytokine therapies Checkpoint inhibitor therapies Stimulatory antibodies
How does a polyclonal antibody work?
Immunisation with antigen will
typically lead to a polyclonal response
Many different B cell clones will generate antibodies
specific for the antigen
A number of epitopes will be bound by antibody
How does the monoclonal antibody rituximab work?
Specific for the CD20 molecule on the cell surface of a small sub-population of B cells
How does infliximab work?
Tumour Necrosis Factor Inhibitor
Chimeric antibody that blocks the function of tumour necrosis factor alpha (TNF)
TNF is a pro-inflammatory cytokine that stimulates an acute phase reaction
How does herceptin/trastuzumab work?
Treatment of human growth epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer
The antibody binds HER2 on cancer cells and marks them out for destruction by the immune system
